When applied to populations of patients believed to have immune complex (IC) disease, many of the assays designed to measure circulating IC detect only low and intermediate size (7S-18S) material. This is also true with assays designed to measure C3-bearing IC, even though it is widely believed that IC must be greater than 19S to activate complement. However, the products generated by the formation of IC in serum have never been delineated. Recent work has established that IC formed in the presence of complement differ markedly in size from IC formed in its absence, and that C3b receptors of red blood cells also play a role in determining the size of IC. We have shown that low molecular weight C3-bearing IgG is formed by the interaction of nascent C3b and bystander serum IgG as a result of complement activation. A major objective of this proposal is to delineate the size and source of all C3-bearing immunoglobulin generated in serum during the formation of IC under conditions which take these facts into account and thus approximate the in vivo formation of IC. In addition, the generation of C3-bearing immunoglobulin products in serum during alternative pathway activation will be investigated. In rheumatoid arthritis, the presence of IgG rheumatoid factor (RF) in the synovial fluid of patients with active joint disease is well documented and large complexes of IgG RF are strongly implicated in the pathogenesis of joint disease. IgG RF is also detected in the serum of rheumatoid arthritis patients and although an association between serum IgG RF and vasculitis has been observed, no role has been established for IgG RF in the etiology of the condition. Our data suggest that a major marker of clinical activity in SLE patients is the presence of RF in serum. In patients with the most active disease, we find only low molecular weight rheumatoid factor, most likely IgG RF. We wish to extend these studies and to examine the possibility that intermediate size complexes of IgG RF together with IgM RF will activate complement, in an effort to clarify the role of these substances in rheumatic diseases.